We hypothesize that human leptin has key roles in the regulation of endocrine and metabolic function. The goal of this hypothesis-driven, patient oriented study is to elucidate the endocrine (and metabolic) long-term effects of human leptin. This is a competitive renewal of a study in which we recruited and are currently providing leptin replacement treatment to the only adult individuals identified in the world so far who have a genetically-based, complete deficiency of leptin. These individuals, from a large and highly consanguineous Turkish pedigree, are homozygous for a leptin gene mutation consisting of a C_T substitution in codon 105 of the leptin gene, resulting in an Arg_Trp replacement in the mature protein. This causes a premature stop codon and leads to the same aminoacid substitution as that found in the leptin gene of the ob/ob mouse. Individuals who are homozygous for this mutation are morbidly obese and hypogonadic. As they receive leptin replacement, patients are undergoing weight loss, with marked increases in 24-h fat oxidation. They also have evidence of clinical improvement in endocrine function. This application brings together four research groups with an outstanding history of productive collaborations: Julio Licinio, M.D., UCLA, will oversee the continued longitudinal leptin replacement treatment of these subjects and will conduct rigorous and detailed neuroendocrine studies. Eric Ravussin, Ph.D., Pennington Biomedical Research Center, will study metabolic function. Johannes D. Veldhuis, M.D., University of Virginia, will provide expertise in endocrine data analysis. Metin Ozata, M.D., Gulhane Medical School, Ankara, Turkey, will oversee patients' treatment and health care while they are in Turkey. This study will make it possible for this highly experienced and crossdisciplinary group of investigators to rigorously assess the long-term effects of human leptin in the only adult subjects identified so far who are homozygous for a functional leptin gene mutation. This unique experimental paradigm can contribute to elucidate important aspects of the biology of human leptin. Discontinuation of this study would be highly deleterious, not only for the patients, but also for our understanding of the long-term effects of leptin in humans.